Fibrosis is characterized by an excessive accumulation of collagen in the extracellular matrix of the involved tissue. It is a long-standing and challenging clinical problem for which no effective treatment is currently available. The production of collagen is a highly regulated physiological process, the disturbance of which may lead to the development of tissue fibrosis. The formation of fibrous tissue is part of the normal beneficial process of healing after injury. In some cases, however, an abnormal accumulation of fibrous material can severely interfere with the normal function of the affected tissue or even cause the complete loss of function of the affected organ.
Liver fibrosis, for instance, represents a major medical problem with significant morbidity and mortality. In a variety of liver diseases, chronic injury leads to progressive fibrosis that the liver is able to compensate for over as long as 20-30 years; eventually, however, patients begin to experience symptoms and signs of liver failure due to severe fibrosis and cirrhosis. Worldwide chronic viral hepatitis infections, particularly by Hepatitis B and C virus, represent the major cause of liver fibrosis; however, within the United States chronic alcohol consumption has traditionally been the leading cause of hepatic fibrosis and cirrhosis. Currently, with the rapid increase in the prevalence of obesity in the general population, non-alcoholic fatty liver disease (NAFLD) is becoming the most prevalent condition associated with liver fibrosis and may become the leading cause of liver fibrosis associated morbidity and mortality in coming years. Other known causes of liver fibrosis include parasitic infection, autoimmune diseases, iron or copper storage disorders, and biliary obstruction. Liver fibrosis can be classified as a wound healing response to a variety of chronic stimuli that is characterized by an excessive deposition of extracellular matrix proteins, of which type I collagen predominates. This excess deposition of extracellular matrix proteins disrupts the normal architecture of the liver resulting in structural and functional damages to the organ. If left untreated, liver fibrosis can progress to liver cirrhosis ultimately leading to organ failure and death. Many other debilitating and potentially fatal diseases also lead to fibrosis of organs such as the intestine, kidney, heart, and lung.
Because of the pivotal role of collagen production during fibrosis, many studies have focused on the regulation of collagen expression and proliferation of fibroblasts, the major cell type responsible for collagen synthesis. In the liver, the hepatic stellate cell (HSC) is the primary fibrogenic cell type.
A variety of compounds have been identified as anti-fibrosis agents via different mechanisms of action, including the suppression of collagen expression. For example, pantethine (D-bis-(N-pantothenyl-β-aminoethyl)-disulfide) has been reported to be effective for the inhibition of hepatic fibrosis (U.S. Pat. No. 4,937,266); a hydrazine derivative, benzoic hydrazide, has been shown to be a powerful antifibrotic agent (U.S. Pat. Nos. 5,374,660 and 5,571,846); the use of angiotensin inhibitors in combination with nitric oxide stimulators to inhibit the progression of fibrosis is disclosed in U.S. Pat. Nos. 5,645,839 and 6,139,847; 6,005,009 describes methods using certain pyridoxal benzoyl hydrazones or their analogs for inhibiting fibrosis; U.S. Pat. No. 6,117,445 describes the use of A1 adenosine receptor antagonists and/or P2X purinoceptor antagonists for treating or preventing fibrosis and sclerosis. More recently, somatostatin agonists, hepatocyte growth factors (HGFs), chymase inhibitors, and antagonists of IL-13 have been reported to effectively inhibit fibrosis (U.S. Pat. Nos. 6,268,342, 6,303,126, 6,500,835, and 6,664,227).
The farnesoid X receptor (FXR), also known as the bile acid receptor (BAR) and NR1H4, is a member of the nuclear receptor superfamily of ligand-activated transcription factors and forms, with retinoid X receptor (RXR), a heterodimer receptor crucial for bile acid homeostasis (Forman et al., Cell 81:687-693, 1995; Lu et al., J. Biol. Chem., 17:17, 2001). FXR is expressed in various tissues including the liver, kidney, intestine, colon, ovary, and adrenal gland (Forman et al., Cell 81:687-693, 1995).
Containing a conserved DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD), FXR binds to and becomes activated by a variety of naturally occurring bile acids, including the primary bile acid chenodeoxycholic acid (CDCA) and its taurine and glycine conjugates (Makishima et al., Science 284:1362-1365, 1999; Parks et al., Science 284:1365-1368, 1999; Wang et al., Mol. Cell., 3:543-553, 1999). Upon activation, the FXR-RXR heterodimer binds the promoter region of target genes and regulates the expression of several genes involved in bile acid homeostasis. For example, the activation of FXR in the liver leads through the direct induction of the nuclear receptor short heterodimer partner (SHP) to the reduced expression of CYP7A, a gene encoding an enzyme catalyzing the rate-limiting step in bile acid synthesis (Schwartz et al., Curr. Opin. Lipidol., 9:113-119, 1998); whereas the activation of FXR in the intestine leads to increased expression of a bile acid-binding protein (I-BABP), which is involved in the active transport of bile acids in the ileum (Kanda et al., Biochem. J., 330:261-265, 1998). For a more detailed list of FXR-regulated genes, see, e.g., WO 03/016288, pages 22-23.
Because of the importance of FXR in bile acid homeostasis, FXR-activating ligands have been proposed for use to treat a variety of cholestatic liver diseases and conditions where the normal enterohepatic bile flow is blocked or has otherwise ceased (see, e.g., WO 02/072598 and WO 03/090745).
While not intending to be bound to any particular theory, the present inventor revealed that FXR activation can down-regulate collagen synthesis and resulting fibrosis through a mechanism involving SHP and other FXR target genes. Thus, FXR-activating ligands are effective anti-fibrosis agents in tissues and organs where FXR is present, such as liver, kidney, intestine, etc. The present disclosure provides a new method for preventing, treating and/or reversing fibrosis, based on the surprising discovery of previously unknown properties of FXR-activating ligands.